476314-47-3Relevant academic research and scientific papers
Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor
He, Yali,Yin, Donghua,Perera, Minoli,Kirkovsky, Leonid,Stourman, Nina,Li, Wei,Dalton, James T,Miller, Duane D
, p. 619 - 634 (2007/10/03)
While nonsteroidal androgen receptor (AR) antagonists have been known for many years, and used in the clinic for the treatment of hormone dependent prostate cancer, very little is known about nonsteroidal AR agonists. We designed and synthesized a series of chiral bicalutamide analogs, which bear electron-withdrawing groups (either a cyano or a nitro group at the 4-position and a trifluoromethyl group at the 3-position) in the aromatic A ring, and different substituents at the para position in the aromatic B ring of the parent molecule. We also synthesized a series of racemic bicalutamide analogs, which have a trifluoromethyl group instead of a methyl group at the R2 position. We examined AR binding affinities of our compounds in a competitive binding assay with a radiolabeled high affinity AR ligand, 3H-mibolerone, and also measured their abilities to stimulate AR-mediated transcriptional activation in a cotransfection assay. These studies demonstrated that (1) nonsteroidal ligands can be structurally modified from known nonsteroidal antiandrogens to generate ligands capable of activating AR-mediated transcriptional activation. (2) R-isomer analogs exhibit higher AR binding affinity and more potent functional activity than their corresponding S-isomers in all cases. (3) All sulphide analogs show higher AR binding affinity and more potent functional activity than their corresponding sulphone analogs, with the exception of ligand R-8. Those ligands which exhibit high AR binding affinity and potent functional activity for human AR may provide effective clinical uses for male fertility, male contraception, and hormone replacement therapy.
Non-steroidal agonist compounds and their use in male hormone therapy
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, (2008/06/13)
The present invention relates to a nonsteroidal agonist compound having the formula: where R1, R2, and R3 are the same or different and are a hydrogen, a nitro, a cyano, a carbamoyl, a halogen, a perfluoroalkyl, a haloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, or a beta -chloroethylamine; R4 is a hydrogen, an alkyl, or is joined to R5; R5 is a hydrogen, a hydroxy, an alkoxy, an acyloxy, an amino, an alkylamino, a halogen, an alkyl, a haloalkyl, or is joined to R4; R6 is a hydrogen, an alkyl, or a haloalkyl; A1 and A2 is the same or different, each is direct link or an alkylene; X1 is an oxygen, a sulfur, a sulphinyl, a sulphonyl, an amino, an alkylimino, or an alkylene; R7 is a hydrogen, a halogen, an alkoxy, a haloalkoxy, an acyloxy, a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, an amino, an alkylimino, an alkylamido group, a haloalkylamido group, or a phenyl optionally substituted with a halogen, a nitro group, an alkyl, a haloalkyl, a cyano, a hydroxyl, a carboxylic group, an amino, an alkylamino group, a dialkylamino group, a bisalkylamino group, a haloalkylamino group, a dihaloalkylamino group, a bishaloalkylamino group, an acylamido group, a diacylamido group, an alkylacylamido group, a haloacylamido group, a bis(haloacyl)imido group, or an alkylhaloacylamido group. The present invention further relates to a method of producing the non-steroidal agonist compound, a composition containing the non-steroidal agonist compound, and methods of binding an androgen receptor, suppressing spermatogenesis, and providing hormonal therapy for androgen-dependent conditions.
